8-Hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines

ABSTRACT

8-Hydroxy-6,7-(2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines are prepared by a reaction sequence whose key is a dual cyclization forming the 3-benzazepine ring and fused thereto a dihydrofuran.

This invention comprises a group of new chemical compounds whosestructures comprise a 2,3,4,5-tetrahydro-1H-3-benzazepine skeletonsubstituted at 1 by a phenyl or substituted phenyl, at 6,7 by acondensed dihydrofuro ring and at 8 by a hydroxy. These compounds are,therefore,8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.They have peripheral dopaminergic activity particularly renalvasodilating activity.

The compounds of this invention are represented by the followingstructural formula: ##STR1## in which R is hydroxy or methoxy, R₁ ishydrogen, methyl or allyl and R₂ is hydrogen, methoxy, hydroxy,methylthio, methyl, trifluoromethyl or halo such as fluoro, chloro,bromo or iodo.

A sub-group of this invention comprises the compounds of Formula I inwhich R and R₂ are both hydroxy.

The pharmaceutically acceptable acid addition salts having the utilityof the free bases of Formula I, prepared by methods well known to theart, are formed with both inorganic or organic acids, for example:maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methane sulfonic, ethane disulfonic, acetic,oxalic, propionic, tartaric, salicylic, citric, gluconic, aspartic,stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic,phosphoric and nitric acids. The hydrohalic and especiallymethanesulfonic acid salts are of particular utility.

Also included in this invention are O-lower alkanoyl esters of thecompounds of Formula I having from 2-8 carbon atoms in each alkanoylgroup such as acetyl, isobutyryl, propionyl, isovaleryl, n-heptanoyl andothers. When more than one hydroxy substituent is present it is moreconvenient to have the same alkanoyl group present at each position. Theester derivatives are prepared by treating the hydroxy parent of FormulaI protected if necessary at position 3 by a N-benzyl substituent or byan acid addition salt with either a stoichiometric amount or a slightexcess of an acyl halide or anhydride in the presence of an organic baseoptionally in an organic solvent.

It will be obvious to one skilled in the art that the compounds ofFormula I may be present as diastereo-isomers which may be resolved intod, l optical isomers. Resolution of the optical isomers may beconveniently accomplished by fractional crystallization of their saltswith optically active acids from appropriate solvents. Specific methodsof resolution useful for 3-benzazepines are disclosed in Swiss Pat. No.555,831. Unless otherwise specified herein or in the claims, it isintended to include all isomers, whether separated or mixtures thereof.Where isomers are separated, the desired pharmacological activity willusually predominate in one of the isomers. However usually the mixtureof isomers is used for the purpose of this invention.

The compounds of this invention are prepared by the following reactionsequence: ##STR2##

In the above flow diagram R and R₁ are as defined above for Formula I.R₃ is also as defined but should not be hydroxy.

2-Allyl-3,4-dimethoxyphenylacetonitrile (II) is prepared by reacting aknown 2-allyl-3,4-dimethoxybenzyl halide with an alkali metal cyanide inan inert, dipolar aprotic solvent with heat. The resultingphenylacetonitrile is reduced using any specific nitrile reducing agentwhich does not act on the allyl group such as aluminum hydride intetrahydrofuran at ambient temperature to give2-allyl-3,4-dimethoxy-β-phenethylamine (III). Other catalyst are lithiumaluminum hydride in tetrahydrofuran, triethyllithiumborohydride, orsodium bis(2-methoxyethoxy)-aluminum hydride. The amine is condensedwith an optionally substituted methyl or ethyl mandelate, mostconveniently by heating on a steam bath without solvent for 6-12 hours,to give an optionally substitutedN-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]mandelamide (IV). The amide isthen reduced using a specific amide reducing agent known to the art suchas lithium aluminum hydride or especially sodiumbis(2-methoxyethoxy)-aluminum hydride in a benzenoid solvent such asbenzene, toluene or xylene or tetrahydrofuran at reflux temperature togive an optionally substitutedN-(2-hydroxy-2-phenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]-amine(V). As an alternative to the mandelamide route to the secondary amine(V) the phenethylamine (III) may be reacted with the appropriate styreneoxide with heat at 90°- 110° for from 1-3 hours.

The key reaction of the reaction sequence is the double cyclization ofthe secondary amine (V) to form the benzazepine and furan rings (V→VI).Good yields are realized from reacting the secondary amine (V) in thepresence of sulfuric acid-trifluoroacetic acid at ambient temperatureuntil the reaction is complete. Alternatively other cyclizing agentsknown to the art may be used such as hydrohalic acids such as 48%hydrobromic acid at 100° or hydriodic acid at reflux. Of course suchhydrohalic acid cyclization will also split any methoxy substituentssuch as at 8 or on the 1-phenyl ring and thereby give a mixture ofproducts which may be separated by standard isolation methods. Ingeneral the use of mild reaction conditions is preferred to minimizeside reactions.

The8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinesof Formula VI are of prime use as intermediates. For example, they maybe demethylated by reaction with boron tribromide or hydrobromic acid togive the hydroxylated products of Formula I.

Also the compounds of Formula VI in which R₁ is hydrogen may beN-alkylated by reactions standard in the art such as using allylchloride, bromide or iodide as well as methyl iodide in an inert organicsolvent such as acetonitrile in the presence of a tertiary organic basesuch as triethylamine, pyridine or dimethylaniline. The N-alkylatedcompounds are then demethylated as described above to give the compoundsof Formula I in which R₁ is methyl or allyl.

The compounds of this invention have peripheral dopaminergic activity asmeasured by monitoring mean arterial blood pressure (MAP), mean renalblood flow (RBF), renal vascular resistance (RVR) and heart rate (HR) inthe normal anesthetized dog. For example6,7-(2-methyl-2,3-dihydrofuro)-8-hydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide (A) gave the following results:

    ______________________________________                                        Compound                                                                              Dose          % Change                                                μg/kg/min  MAP     RBF      RVR    HR                                      ______________________________________                                        dopamine                                                                              3          -6.4*   +17.8*                                                                              -19.9* - 9.1*                                A       3         0       + 3.9  - 4.2  0                                             30        -3.3    + 7.4* - 9.4* 0                                             300       -6.0*   +3.4   -9.2*  -12.9*                                ______________________________________                                         *significant for 2 dogs                                                  

The data demonstrate increased renal blood flow and decreased renalvascular resistance at 30 μg/kg/min. This result is an indication ofperipheral dopaminergic activity and resultant improvement incardiovascular function.

The same compound did not demonstrate significant central dopaminergicactivity in the rotation test in lesioned rats at 10.0 mgm/kgintraperitoneally which is a standard test for anti-parkinsonismactivity.

The pharmaceutical compositions of this invention havingantihypertensive activity more especially peripheral dopaminergicactivity are prepared in conventional dosage unit forms by incorporatinga compound of Formula I, an isomer or a pharmaceutically acceptable acidaddition salt or ester derivative thereof, with a nontoxicpharmaceutical carrier according to accepted procedures in a nontoxicamount sufficient to produce the desired pharmacodynamic activity in asubject, animal or human. Preferably the compositions will contain theactive ingredient in an active but nontoxic amount selected from about50 mg to about 500 mg. preferably about 75-250 mg of active ingredientper dosage unit but this quantity depends on the relative potency of thebasic compound, the specific biological activity desired, the route ofadministration, oral or parenteral, and the condition of the patient.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Exemplary of liquid carriers are isotonic saline forparenteral use or syrup, peanut oil, olive oil, water and the like forsoft gelatin capsules. Similarly the carrier or diluent may include anytime delay material well known to the art, such as glyceryl monostearateor glyceryl distearate alone or with a wax. Such sustained releaseproducts as well as derivatives which may be gradually metabolized tothe active parent can be employed to prolong the unique biologicalactivity of the compounds of this invention.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier for oral administration is used the preparation can be tableted,placed in a hard gelatin capsule in powder, regular or sustained releasepellet form, or in the form of a troche or lozenge. The amount of solidcarrier will vary widely but preferably will be from about 25 mg toabout 1 g. If a liquid carrier is used, the preparation will be in theform of a syrup, emulsion, soft gelatin capsule, sterile injectableliquid such as an ampul, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to give the desired end product.

The method of producing peripheral dopaminergic activity in accordancewith this invention comprises administering orally or parenterally to asubject in need of such activity a compound of Formula I or apharmaceutically acceptable acid addition salt thereof, usually combinedwith a pharmaceutical carrier, in a nontoxic amount sufficient toproduce said activity as described above. The route of administrationmay be any route which effectively transports the active compound to theperipheral dopamine receptors which are to be stimulated such as orallyor parenterally, the oral route being preferred. Advantageously, equaloral doses within the ranges given above will be administered severaltimes, such as from two to five times, a day, with the daily dosageregimen being selected from about 50 mg to about 1.0 g., preferably75-500 mg/kg for oral dosage units. When the method described above iscarried out dopaminergic activity is produced. For an average size humanfor the preferred species (A) a preferred oral dose to showanti-hypertensive activity would be selected from the range of fromabout 100-250 mg for each dosage unit adapted for oral administration tobe administered from 1-5 times daily.

The following examples are designed solely to illustrate the preparationand use of the compounds of this invention. The temperatures areCentigrade. Other variations of these examples will be obvious to thoseskilled in the art.

EXAMPLE 1

A mixture of 41.4 g (0.183 mole) of 2-allyl-3,4-dimethoxybenzyl chloride[R. Schwarz et al., Monatsh. 84 595 (1953)] and 210 ml ofdimethylformamide was mixed with 10.5 g (0.214 mole) of sodium cyanide.The mixture was heated at 60° for 1.5 hours. Water (100 ml) was addeduntil the solid present dissolved. The reaction mixture was then pouredinto 1 l. of water. The diluted reaction mixture was extracted twicewith ether. The ether extract was backwashed with water, dried andevaporated to give 37.9 g. (75.6%) of oily2-allyl-3,4-dimethoxyphenylacetonitrile. Nuclear magnetic resonancespectrum (NMR) checked.

The acetonitrile (15.25 g., 0.07 mole) in 100 ml of dry tetrahydrofuranwas added dropwise over 20 minutes to a previously prepared solution of3.15 g. (0.105 mole) of aluminum hydride in 140 ml. of drytetrahydrofuran under argon. After stirring for 1.25 hours at ambienttemperature, the mixture was worked up by adding sequentially 3.8 ml. ofwater, 3.8 ml. of 10% sodium hydroxide and 10 ml. of water. Afterseparating the solid, the filtrate was evaporated to give2-allyl-3,4-dimethoxy-β-phenethylamine as an oil. NMR checked.

A mixture of 12.7 g. (0.058 mole) of the phenethylamine and 11.3 g.(0.058 mole) of methyl 4-methoxymandelate was heated on a steam bath for8 hours. The cooled reaction mixture was dissolved in ethyl acetate. Theorganic extract was then washed twice each with dilute hydrochloric acidand sodium bicarbonate solution. The dried organic extract wasevaporated to giveN-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]-4-methoxymandelamide, 20.6 g.(93%).

A commercial mixture of sodium bis(2-methoxyethoxy)aluminum hydride intoluene (60 ml., 0.23 mole) was added dropwise over a 1 hour period to asolution of the mandelamide (20.6 g.) in 180 ml. of toluene. Thereaction mixture was heated at reflux for 1.5 hours then quenchedcarefully with 20 ml. of water. The solution was filtered and thefiltrate evaporated. The residue was dissolved in methylene chloride.The organic extract was then shaken with dilute hydrochloric acid andsodium carbonate solution. The dried methylene chloride extract wasevaporated to leave a residue which was passed over a silica columnusing 5% methanol-chloroform to give 8.2 g. (39%) of oilyN-[2-hydroxy-2-(4-methoxyphenyl)-ethyl]-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amineas the oily base.

Key NMR absorption (CDCl₃): 2.72 (m, 6, --CH₂ CH₂ NHCH₂ --).

A mixture of 4.5 g. (0.012 mole) of the secondary amine and 34 ml. ofcold trifluoroacetic acid was prepared. After adding 0.97 ml. of conc.sulfuric acid, the reaction mixture was stirred at ambient temperaturefor 60 hours. Anhydrous sodium acetate (1.5 g., 1 eq.) was added.Stirring was continued until the salt dissolved. The organic solvent wasevaporated. The residue was partitioned between ethyl acetate and 10%sodium hydroxide solution. After extracting the alkali layer with ethylacetate, the combined organic extracts were dried and evaporated. Theresidue was extracted with ether. The ethereal extract was dried andtreated with ethereal hydrogen chloride to separate, afterchromatographic purification over silica with 10% methanol chloroform,1.37 g. (30%) of8-methoxy-1-(4-methoxyphenyl-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 236°-239°.

C₂₁ H₂₄ NO₃.HCl.1/2H₂ O Anal. Calcd: C, 65.53; H, 7.07; N, 3.65 Found:C, 65.17; H, 7.16; N, 3.53

Key NMR absorption (CDCl₃): 2.75 (m, 6, CH₂ NHCH₂, ArCH₂ CH); 4.93 (m,1,##STR3##

EXAMPLE 2

A mixture of 2.8 g. (0.0083 mole) of the dimethoxy product of Example 1in 50 ml. of methylene chloride was cooled to -15° at which temperature10 ml. of boron tribromide was added dropwise. A red precipitate formedbut dissolved as the mixture was stirred at ambient temperature for 3hours. The mixture was cooled to -15°. A 1:1 mixture of methanol andmethylene chloride was added to destroy excess boron tribromide. Thesolvents are evaporated. The residue was recrystallized from ethylacetate-ether to give 1 g. of crude8-hydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide. A sample was recrystallized from methanolethyl acetatethen water to give an analytical sample, m.p. 317°.

C₁₉ H₂₀ NO₃.HBr.1/4H₂ O Anal. Calcd: C, 57.51; H, 5.27; N, 3.53 Found:C, 57.73; H, 5.72; N, 3.74

NMR and mass spectrum consistant.

The hydrobromide salt (500 mg.) is neutralized by shaking in sodiumcarbonate solution-ether. The dried ether extract is divided intoaliquots. One is evaporated to give the free base. The other is reactedwith an excess of methan sulfonic acid in ispopropanol to give themethane sulfonic acid salt.

EXAMPLE 3

A mixture of 5.6 g (0.016 mole) of8-methoxy-1-(4-methoxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineand 75 ml. of acetonitrile is mixed with 3.0 ml. of triethylamine and2.2 ml. of allyl bromide. The mixture is heated on the steam bath for 3hours then evaporated. The residue is suspended in water and extractedtwice with ethyl acetate. The extracts are combined, washed with waterthen brine, dried and evaporated to give3-allyl-8-methoxy-1-(4-methoxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineas the base.

The hydrochloride salt is prepared by treating 300 mg. of the 3-allylbase in methanol with ethereal hydrogen chloride.

The remainder of the base (2.7 g.) is dissolved in 55 ml. of methylenechloride, then cooled to -15° at which temperature 6 ml. of borontribromide in methylene chloride is added at that temperature dropwise.After stirring at room temperature overnight, the reaction mixture ismixed with methanol and evaporated. Methanol-ethyl acetate treatmentgives3-allyl-6,7-(2-methyl-2,3-dihydrofuro)-8-hydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 4

A mixture of 25.4 g. (0.116 mole) of2-allyl-3,4-dimethoxy-β-phenethylamine and 22 g. of methyl mandelate isheated on a steam bath for 5 hours. The mixture is worked up asdescribed in Example 1 to giveN-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]mandelamide. This material (40g.) is reduced with an excess of sodium bis(2-methoxyethoxy)aluminumhydride in toluene first at room temperature then at reflux. Working upgivesN-(2-hydroxy-2-phenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine.This compound (6.8 g.) is combined with 50 ml. of cold trifluoroaceticacid then 1.3 ml. of concentrated sulfuric acid. The mixture is stirredat room temperature for 2 days. Working up as described gives8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepineas the base. Treating 1.2 g. of the 8-methoxy compound with an excess ofboron tribromide in methylene chloride first at -20° then at roomtemperature for 5 hours gives the desired product8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

EXAMPLE 5

A mixture of 3.5 g. of8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-1phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(prepared as in Example 4), 15 ml. of formic acid and 10 ml. offormaldehyde is heated at reflux for 24 hours. The reaction mixture isevaporated to dryness. 6 N Hydrochloric acid (20 ml.) is added to theresidue and the mixture is again evaporated. The residue is treated with20 ml. of 10% sodium hydroxide solution. The mixture is extracted withether. After drying and evaporation of the ether extract,8-methoxy-3-methyl-6,7-(2-methyl-2,3-dihydrofuro)-1-phenyl-2,3,4,5tetrahydro-1H-3-benzazepinehydrochloride is recovered. Treatment with boron tribromide as inExample 4 gives the 8-hydroxy congener as the base and as thehydrobromide.

EXAMPLE 6

3-Allyl-8-dihydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide (1.0 g.) is slurried in 200 ml. of trifluoroacetic acidthen 1.29 ml. of acetyl bromide is added. The mixture is heated atreflux for 2 hours then stirred for 2 hours. After evaporation todryness the residue is taken up in benzene and concentrated to give3-allyl-8-acetoxy-1-(4-acetoxyphenyl-6,7-(2-methyl-3,4-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide.

Similarly the isobutyryloxy, propionyloxy, isovaleryloxy, n-butyryloxy,n-heptanoyloxy and other higher derivatives are prepared at the8-hydroxy or the phenyl hydroxy groups.

EXAMPLE 7

Using the reaction and isolation methods of Examples 1 and 2:

A. 2-allyl-3,4-dimethoxy-β-phenethylamine and methyl 2-fluoromandelategive N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]2-fluoromandelamide,N-(2-hydroxy-2-fluorophenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine,1-(2-fluorophenyl)-8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineand1-(2-fluorophenyl)-8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinetogether with its hydrobromide salt.

B. 2-allyl-3,4-dimethoxy-β-phenethylamine and ethyl 3-methylmandelamidegive N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl] 3-methylmandelamide,N-(2-hydroxy-2,3-methylphenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine,1-(3-methylphenyl)-8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepine,1-(3-methylphenyl)-8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinetogether with its hydrochloride salt.

C. 2-allyl-3,4-dimethoxy-β-phenethylamine and ethyl4-trifluoromethylmandelate giveN-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]4-trifluoromethylmandelate,N-(2-hydroxy-2-4-trifluoromethylphenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine,8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-1-(4-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-(4-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepinetogether with its sulfate salt.

D. 2-allyl-3,4-dimethoxy-β-phenethylamine and methyl 4-chloromandelategives N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]4-chloromandelate,N-(2-hydroxy-2-4-chlorophenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine,1-(4-chlorophenyl-8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineand1-(4-chlorophenyl)-8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinetogether with its hydrobromide salt.

E. 2-allyl-3,4-dimethoxy-β-phenethylamine and methyl4-methylthiomandelate giveN-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]4-methylthiomandelate,N-(2-hydroxy-2-4-methylthiophenylethyl)-N-[2-(2-allyl-3,4-dimethoxyphenyl)ethyl]amine,8-methoxy-6,7-(2-methyl-2,3-dihydrofuro)-1-(4-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand8-hydroxy-6,7-(2-methyl-2,3-dihydrofuro)-1-(4-methylthiophenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineas its hydrobromide salt.

EXAMPLE 8

    ______________________________________                                        Ingredients             Mg. per Capsule                                       ______________________________________                                        8-Hydroxy-1-(4-hydroxyphenyl)-6,7-(2-                                                                 150 (free base)                                       methyl-2,3-dihydrofuro)-2,3,4,5-                                              tetrahydro-1H-3-benzazepine methane                                           sulfonic acid salt                                                            Magnesium stearate       2                                                    Lactose                 200                                                   ______________________________________                                    

The ingredients are thoroughly mixed and placed into hard gelatincapsules. One capsule is administered orally to patients in need ofperipheral dopaminergic activity from 1-5 times daily.

What is claimed is:
 1. A compound of the structural formula: ##STR4## inwhich R is hydroxy or methoxy, R₁ is hydrogen, methyl or allyl and R₂ ishydrogen, methoxy, hydroxy, methyl, methylthio, trifluoromethyl or halo;together with a pharmaceutically acceptable acid addition salt orO-lower alkanoyl ester thereof.
 2. The compound of claim 1 being8-hydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3,-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable acid addition salt thereof.
 3. Thecompound of claim 1 being8-hydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepinemethane sulfonate salt.
 4. The compound of claim 1 being8-hydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineas the free base.
 5. The compound of claim 1 being8-methoxy-1-(4-methoxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable acid addition salt thereof.
 6. Thecompound of claim 1 being3-allyl-8-hydroxy-1-(4-hydroxyphenyl)-6,7-(2-methyl-2,3-dihydrofuro)-2,3,4,5-tetrahydro-1H-3-benzazepineor a pharmaceutically acceptable acid addition salt thereof.
 7. Themethod of inducing peripheral dopaminergic activity in a subject in needthereof comprising administering orally or parenterally thereto anontoxic dopaminergic quantity of a compound of claims 1, 2, 3, 4, 5 or6.
 8. The pharmaceutical composition having peripheral dopaminergicactivity comprising a nontoxic dopaminergic quantity of a compound ofclaims 1, 2, 3, 4, 5 or 6 combined with a pharmaceutical carrier.
 9. Themethod of preparing a compound of the formula: ##STR5## in which R₁ ishydrogen, methyl or allyl and R₃ is hydrogen, methoxy, methyl,methylthio, trifluoromethyl or halo, comprising reacting a compound ofthe formula: ##STR6## in which R₁ and R₃ are as defined above, in thepresence of sulfuric acid-trifluoroacetic acid at ambient temperatureuntil reaction is complete.